amorphous solid dispersions: application of spray drying formulations for discovery toxicology...
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Amorphous Solid Dispersions: Application Of Spray Drying Formulations For Discovery Toxicology Studies
Mengwei Hu, James Ormes and Jiang Chang Merck & Co.
2
Presentation Outline
• Challenges in Discovery toxicology formulation development
• General concept of spray dried amorphous solid dispersions
• Integration of spray drying technology in Discovery space
• Case studies of applications of amorphous solid dispersion for Discovery toxicology studies
• Summary
• Acknowledgement
3
Challenges In Discovery Toxicology Formulation Development
• Requirement of higher oral exposure (except for oncology programs) to ensure safety margin:
– Exposures can be limited by• Compound specific properties:
–Solubility–Dissolution rate–Permeability–GI tract stability–First pass effect
• Formulation specific properties:–Maximum feasible dose: limited by feasible concentration,
dosing volume and daily allowed amount of excipients–Release rate
can be significantly improved by formulation strategies
4
Challenges In Discovery Toxicology Formulation Development (continued)
• Prefer solution/suspension formulation– Easiness for dosing especially for rodent species
– Easiness for body weight adjustment
– Besides bioperformance, need to address:• Dosability:
– uniformity, viscosity and syringability
• Stability:
– Physical stability: polymorphism, disproportionation, particle size distribution, pH shift, agglomeration and gelling
– Chemical stability: chemical degradation (hydrolysis, oxidation,compatibility with excipients and photostability)
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Challenges In Discovery Toxicology Formulation Development (continued)
• Narrower choices of excipients– To ensure clear read out of toxicity caused by API.
– Excipients with similar toxicity concern as the API have to be avoided.
– Wider choices for short term study. However, line of sight for long term toxicology study is critical.
– Full knowledge of species specific toxicity of excipients is essential.
– Maximum daily allowed amount of excipients has to be established.
– Concern specific to the therapeutic area: • Example: using lipid based formulations for lipid modifying agents
• Short development time for toxicology formulations
• Limited availability of API
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Toxicology Formulation Strategies
• Solubilization– Ionization by pH adjustment– Salt– Cosolvent– Surfactant– Complexation– Lipid based formulation
• Increase dissolution rate through particle size reduction– Micronization– Nanoparticle
• Improve solubility by converting API to amorphous state and maintaining it at amorphous state (amorphous solid dispersion)
– Hot melt extrusion or melt quenching techniques– Spray drying
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Spray Drying Process
• Mix up liquid feed containing drug, polymer, and optional surfactants in a solution or suspension.• Atomize liquid feed to generate desired droplet formation• Dry droplets (fast drying rate) to generate amorphous, solid particles (from solution)• Collect product from processing gas stream (e.g cyclone & bag filter)
Spray Dried Drug/Polymer
AtomizationGas
Evaporation of Solvent
Heat in
Hotterregion
SprayDroplet
SpraySolution Hot
CoolProcessing Gas
Coolerregion
Credit: Galen Shi
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How Spray Dried Amorphous Solid Enhances Drug Exposure
• Amorphous state has higher free-energy No crystal lattice to breakHigher Thermodynamic Solubility
• Fine particle size Large surface area Improved Kinetic Dissolution
Amorphous solid dispersion is particularly useful for compounds with high crystal lattice energy
Free Energy
Crystalline Drug
Amorphous Drug
GSolvated Drug
G
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Polymer Excipients in Spray Drying
•Polymers stabilize the amorphous state of the drug.
•Enhance super-saturation of the drug upon dissolution by preventing nucleation.
Free Energy
Crystalline Drug
Amorphous DrugAmorphous Drug
w/Polymer
Poor SolubilityStable
Better SolubilityLow Stability
Better SolubilityBetter Stability
Dina Zhang with permission
Patrick Marsac with permission
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Integrate Amorphous Solid Dispersion in the Drug Discovery Process
Challenges:
• Aggressive timeline requires fast turn-around– Rely on high throughput screening and platform approaches
• API supply limitations at various stages of Discovery space– Scaled down process for batch preparation, characterization and
analysis
• Cross-functional collaboration is required– High throughput screening– Formulation preparation– Characterization and analysis– Troubleshooting – Scale up
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Screening For Solvents and Polymers
• Solvent Selection is based on solubility (> 10 mg/mL) and compatibility• Acetone, MeOH, EtOH, IPA, t-BuOH, EtOAc, IPOAc, Toluene, HOAc,
MEK, THF, DCM plus mixing with H2O (up to 25%)
• Polymer Selection• Solvent casting screening in 96-well plate• Polymers: HPMCAS (LF, MF, HF), HPMCP (HP-55), PVP-PVAc(Kollidone
VA64) PVP (Kollidone 90F), Eugragit (L100) and etc.• Surfactants (optional) to further enhance solubility• A small amount of film is formed and characterized by microscopy and
PXRD• Kinetic solubility of dispersed film in FaSSIF
Shanbhag, A. et. al.,International Journal of Pharmaceutics, 351, 209-218 (2008)Moser, J. D. et. al.. American Pharmaceutical Review, Sep/Oct, 2008
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Scaled Down Process
•ProCepT Microspray Drying system provides capabilities of small batch size to accommodate limitation of compound availability in Discovery space:
Batch size: 0.25 – 4000 mL Particle size range: 2- 75 microns Processing yield: ~85% for 25 mg of
product
Information provided by ProCepT
Drying GasInlet
+ Heater
Feed Solution
Cyclone + Collection
Vessel
Drying Chamber
Connecting Tube
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Characterization of Spray-Dried Amorphous Solid Dispersion
• Physical characterization: mDSC, PXRD and TGA
• Chemical characterization: assay and impurity profile
• Solid state stability
• In-use stability in suspending vehicle
• Redisperse study in SGF and FaSSIF
• Maximum feasible concentration determination
• Confirm exposure enhancement by pharmacokinetic studies
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• Platform vehicle:
Suspending agent + Acidifying agent + Wetting agent
• Key Considerations:– Visual wetting, stirability/suspendability/syringability, at low and high
dose (MFC)
– Physically and chemically stable for at least 4 hours
– Well-dispersed and uniform suspension
– Maximum feasible concentration
– Acidifying agent prevents API released from the pH sensitive polymer to ensure in-use physical stability
– Low amount of surfactant is added as a wetting agent but may promote solubilization/dissolution of the API and hence may promote crystallization.
Platform Vehicle and Vehicle Selection
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Limitations of Spray Dried Amorphous Solid Dispersion Formulation
• Solubility and compatibility in organic solvents
• Drug loading limitations (Maximum Feasible Concentration concerns)
• Complexity of workflow in fast-paced Discovery space
• Additional work of scaling up for GLP toxicology studies
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Challenge: Identify a formulation strategy to provide exposure despite the poor solubility (<0.001 mg/mL in SGF and FaSSIF).
In rodents the spray dried amorphous solid dispersion formulation significantly improve exposure relative to alternative formulation strategies.
Case Study #1: Using Spray Dried Amorphous Solid Dispersion Of Compound A For Discovery Toxicology Studies
0.00
4.00
8.00
12.00
16.00
0 4 8 12 16 20 24
PEG/Tw een (200 mpk)20% TPGS (200 mpk)Nanoformulation (100 mpk)Spray Dried Amorphous (100 mpk)
Time (hr)
AU
C
Rodent PK
Spray dried amorphous solid dispersion formulation
J. Ormes, J. Chang, D. Leung, E. Kwong, F. Li
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• Challenges:
1. The compound exhibited polymorphism with numerous crystallinephases (>20) identified and physical phase instability in the conventional formulation
2. The compound exhibited a >30x decrease in solubility from amorphous phase upon identification of a high melting crystalline form (decline from > 0.600 ug/mL to 0.017 ug/mL).
3. Discovery toxicology formulation had to be developed within two weeks to meet program timeline
Case Study #2: Using Solid Dispersion Formulation to Enhance Oral Exposure and Resolve Polymorphism Issues
M. Hu, J. Ormes, J. Chang, E. Kwong, A. Bak, C. Alleyne, S. Lohani
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Case Study #2: Using Solid Dispersion Formulation to Enhance Oral Exposure and Resolve Polymorphism Issues
• Spray Dried formulation provided a physically stable formulation which overcame solubility concerns to provide sufficient exposure for discovery toxicology studies without timeline delay.
unstable53x254221.5Nanosuspension
(wet milling)
stable143x6862.343.8Amorphous Solid
Dispersion
(spray drying)
unstable127x611248
Conventional Formulation
(partially solubilization)
Physical Stability (in vehicle)
Exposure Multiple
AUC(0-x)(μMh)
Tmax (h)Cmax (μM)PK 100 mpk in Rat
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• Spray dried amorphous solid dispersion is a powerful tool for enhancing bioavailability and providing stable amorphous platform formulations in Discovery:
– Spray Drying enables compounds with poor solubility to achieve sufficient oral exposures
– Spray dried amorphous solid dispersion also simplifies formulation strategy for compounds displaying complex polymorphism.
• By utilizing solvent casting screening, scaled down process and platform approach, spray-dried amorphous solid dispersion becomes a feasible formulation strategy in Discovery when API is limited and timeline is short.
Summary
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Acknowledgement
Dennis Leung
Fangbiao Li
Candice Alleyne
Sachin Lohani
Vincent Tong
Lina Liu
Timothy Rhodes
Patrick Marsac
Annette Bak
Justin Moser
Mike Lowinger
Caroline McGregor
Dina Zhang
Elise Miller
Davida Krueger
Elizabeth Kwong
Allen Templeton
Michael Kress
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